Project Summary/Abstract Type 2 diabetes (T2D) disproportionately affects the Veteran population: while 9% percent of the total US population has T2D, 25% of the Veteran population suffers from this disease. Adult ? cell mass normally increases via replication in response to insulin resistance, but failure of ? cell proliferation plus increased ? cell death lead to T2D. T2D incidence increases with age, in part due to a decreased ability of ? cells to respond to proliferative cues as they get older. Our lab identified the FoxM1 transcription factor as a critical regulator of postnatal ? cell replication and discovered that it is induced in response to several ? cell proliferative stimuli. Foxm1 expression in islets declines with age in mice and humans, but activation of FoxM1 in older mouse ? cells increases ? cell proliferation and ? cell mass, while enhancing ? cell function. Thus, our data demonstrate that FoxM1 is limiting in older ? cells and that activating FoxM1 can bypass inherent brakes in ? cell proliferation. Little is known about how proliferative stimuli induce Foxm1. Our lab discovered that connective tissue growth factor (CTGF) induces Foxm1 and adult ? cell proliferation in mouse islets in vivo and ex vivo and in human islets ex vivo. The mechanisms and signaling pathways through which CTGF has these effects are currently unknown This study makes use of unique in vivo mouse models as well as ex vivo studies in both mouse and human islets from different ages. In this proposal we will identify and manipulate CTGF signaling pathways in ? cells as molecular targets for enhancing proliferation and regeneration in adult ? cells. In addition, we explore mechanisms through which FoxM1 activation enhances ? cell proliferation and survival, focusing on the antagonistic prostaglandin E receptors EP3 and EP4, which are reciprocally regulated by FoxM1 in islets. We hypothesize that CTGF acts through integrin ?1 signaling to induce Foxm1 expression and adult ? cell proliferation, and that in the setting of ? cell death, CTGF function is enhanced by macrophage-derived signals. We further hypothesize that FoxM1 activation overcomes age-related changes in ? cell proliferation in part through alterations in prostaglandin receptor activity. In this proposal we will: 1) Identify signaling pathways through which CTGF activates Foxm1 expression and ? cell proliferation; 2) Identify macrophage- derived factors that cooperate with CTGF to enhance ? cell mass regeneration; and 3) Determine the role of prostaglandin EP receptors in ? cell proliferation and survival. These studies are designed to identify molecular targets to enhance proliferation and survival in older ? cells with the goal of increasing functional ? cell mass.